Novel 2{8 2-(1,3-diazacycloalk-2-enyl){9 benzophenone derivatives and novel 1,3-diazacycloalkenyl{8 2,1-A{9 isoindole derivatives

ABSTRACT

Novel 2(2-(1,3-diazacycloalk-2-enyl))benzophenone compounds and novel 1,3-diazacycloalkenyl(2,1-a)isoindole compounds having useful analgesic and psychostimulant properties are prepared inter alia by condensation of o-benzoylbenzaldehydes with aliphatic diamines.

United States Patent [1 1 Metlesics et al.

[ 51 Dec. 30, 1975 Inventors: WernerMetlesics, Clifton; Leo

Henryk Sternbach, Upper Montclair, both of NJ.

Assignee: Hoiimann-La Roche Inc., Nutley,

Filed: July-30, 1974 Appl. No.: 493,020-

Related 0.8. Application Data Division of Ser. No. 639,315, May 18, 1967, Pat. No. 3,888,846, which is a continuation-in-part of Ser. No. 626,965, March 30, 1967.

US. Cl. 260/239 BC; 260/251 R; 260/309.6; 260/570 AB; 260/570 R [51] Int. Cl. C07D 243/04 [58] Field of Search 260/570 R, 570 AB, 309.6, 260/239 BC, 251 R [56] References Cited UNITED STATES PATENTS 3,494,964 2/ 1970 Hargrave 260/570 R 3,712,892 1/1973 lnaba et al 260/570 AB Primary Examiner-Lewis Gotts Assistant Examiner-D. R. Phillips Attorney, Agent, or Firm--Samuel L. Welt; Bernard S. Leon; William G. lsgro [57] ABSTRACT Novel 2[ 2-( l ,3-diazacycloalk-2-enyl)]benzophenone compounds and novel l,3-diazacycloalkenyl[2,la]isoindole compounds having useful analgesic and psychostimulant properties are prepared inter alia by condensation of o-benzoylbenzaldehydes with aliphat ic diamines.

1 Claim, No Drawings RELATED Ai PLlCATlONS OH This is a division, of application Ser. No. 639,315, filed May 18, l967, now US. PaLNo. 3,888,846 which 0 s in turn is a continuation-in-part ofU.S. Pat. application Ser. No. 626,965, filed Mar. 30, 1967.

BRIEF SUMMARY OF THE lNVENTlQN This invention relates to a novel class of 2[2-(l,3- diazacycloalkQ-enyl)lbenzophenones and novel 1,3- diazacycloalkenyl[2,l-a]isoindoles, novel processes t and intermediates for the preparation of said novel wherein R R R R and B each have the same products and derivatives thereof and to the use of said meaning as hereinabove. novel compounds as pharmaceuticals. More particu- The invention includes both tautomeric isomers as larly, the invention in its product aspect relates to novel well as mixtures thereof. Tautomeric mixtures can be compounds of the formula represented schematically as R; B R; na

I II

wherein R,, R R R and B each have the same m c B meaning as hercinabove.

Nil Re C o DETAILED DESCRIPTION In one product aspect this application pertains to the 4s 3 novel compounds of formulas l and ll and derivatives thereof. Of particular interest are the compounds of I formulas l and ll wherein B represents the group wherein B represents an alkylene chain of 2 to 4 carbon atoms in which one or more of the hydro- 5O gens can be replaced by lower alkyl; and R R R, R, R and R are each independently selected from the E group consisting of hydrogen, halogen. lower alkyl, 1

lower alkoxy, hydroxy and trifluoromethyl and pharmaccutically acceptable said addition salts 55 thereof. 6

Compounds of formula I can undergo a prototropic and R and R are each independently hydrogen or shift to form compounds of the formula loweralkyl, i.e., compounds of the formulas N-C'!H-R5 I CN-CH-R R II I -CH-R u-ca-a R: R2

wherein R R R and R, each have the same meaning as hereinabove; and R and R are each independently hydrogen or lower alkyl and their pharmaceutically acceptable acid addition salts and tautorneric mixtures.

Compounds of formulas La and "-21 wherein R R R and R are each hydrogen; i.e.. compounds of the o I-d formulas 7 e I N- Ha N-CHz R4 v I 1-1, II-b wherein R, and R each have the same meaning as wherein R,, R R R and B each have the same meanhereinabove ing as hereinabove; and R, is lower alkyl. and their pharmaceutically acceptable acid addition in still another product aspect this application persalts and tautomeric mixtures constitute a preferred 3o tains to novel intermediates which will be more fully group. described with reference to the several processes for v the preparation of compounds of formulas l and H. In another product aspect this application pertains to In one Of its aspects this application pertains to the the mixed ethers obtained from compounds of formula preparation of compounds of formulas i. ll and ll-d I1 and lower alkanols, i.e.. compounds of the formula 35 according to the following reaction sequence.

on: on 32 :CHOH

wherein R 12 R R R and B each have the same meaning as hereinabove.

The diol starting materials of formula V are known compounds or are readily obtainable in analogy to the preparation of the known compounds. The diol starting materials can be readily converted to the dicarbonyl intermediates of formula W by oxidation techniques which are known per se such as, for example, using selenium dioxide and the like. as the oxidizing agent or by employing other oxidizing systems such as chromium trioxide in pyridine.

Treatment with an oxidizing agent can be conveniently carried out in an organic solvent such as. for example. dimethylformamide. dimethylsulfoxide; hydrocarbon solvents such as benzene, toluene; alkanols. c.g.. the lower alkanols. methanol. ethanol. etcs. acetic acid and the like. The oxidationreaction is preferably carried out at an elevated temperature suitably at a temperature between about room temperature and about lSC.

The intermediates of formula IV are themselves novel compounds and thus also constitute part of this invention. The intermediates of formula W are readily condensed with diamines of the formula wherein B has the same meaning as hercinabove by mixing the components or by reacting them in the presence of an organic solvent such as benzene. toluene; alcohols such as lower alkanols and the like. The condensation is conveniently carried out at room temperature or above. preferably at a temperature between about C. and 150C. Alternatively. the diamine reactant of formula Xll' can be employed as a salt thereof in which case the reaction is conducted by heating the mixture of reactants to a melt.

The reaction products. i.e.. the compounds of formula lll. can be readily oxidized. for example. by treatment with an oxidizing agent such as hydrogen peroxide or by exposure to gaseous oxygen at room temperature to give the peroxides of formula ll-c which are readily reduced to the corresponding end products. The oxidation is conveniently carried out in an organic solvent such as alcohols. dimethylformamide. etc. at room temperature. Higher or lower temperatures. e.g.. between about 20C. and 100C.. can also be employed.

Since the peroxide intermediates readily undergo reduction. the reaction mixture obtained upon treatment of a compound of formula ill with an oxidizing agent will ordinarily contain the end products along with the peroxide intermediate of formula ll-c. Complete reduction of the peroxide can be accomplished without separating it from the reaction mixture and. in a preferred embodiment, the oxidation product is submitted directly to treatment with a reducing agent. lt desired. however. the peroxide intermediate of formula ll-c can be separated from the reaction mixture obtained upon treatment of a compound of formula ill with an oxidizing agent by any of the usual techniques e.g.. chromatographic separation. fractional crystallization. etc.

The reduction of the peroxide is conveniently carriec out by employing any reducing agent conventionally used for the reduction of peroxides such as sodiurr sulflte, trialkylphosphite. etc. preferably in the pres ence of an organic solvent such as an alcohol. e.g. methanol. ethanol. ete.; dimethylformamide and tht like. or when using a salt of the peroxide. the reductiot can be carried out in an aqueous solvent. e.g.. in an aqueous alcoholic solvent. The reduction is suitabl carried out at room temperature or above. preferabl at a temperature between about 2C. and C.

As noted above. the hydroxyl proton of a compount of formula ll can undergo a prototropic shift to forn the corresponding isomeric end product of formula 1 in solution the product obtained upon oxidation an reduction of an intermediate of formula ill will ordinat ily be a mixture of the tautomerie forms I and ll. Th relative amounts of the isomeric forms present is de pendent upon such factors as the solvent system err ployed. the pH of the medium and the particular proc uet. i.e.. the meaning of B. R.. R,. R; and R. in formula I and ll. For example. in a solution of chloroform th product obtained upon oxidation and reduction of 2.1 dihydro-5-phenyl-5H-imidazo[2.l-a]isoindole contair a mixture of the isomers 2.3-dihydro-5-hydroxy-5-pht nyl-5H-imidazo[2.l-alisoindole and 2-(2-benzoy phenyl)-2-imidazoline in a ratio of about lzl. The aci addition salts isolated in the ordinary manner from ti reaction product of the oxidation and reduction 1 2.3 dihydro-5-phenyl-5H-imidazo-ll.l-alisoindoie at ordinarily obtained as structure I.

7 Compounds of formula Il-d are prepared from compounds of formula ll by treating an acid addition salt cg. the hydrochloride, hydrobromide or the like. of a formula II compound with a lower alkanol preferably at an elevated temperature. The etherification can be suitably carried out using the lower alkanol as solvent or in the presence of an inert organic solvent such as other and the like and preferably at a temperature between about room temperature. and the reflux temperature of the reaction mixture, i.e., up to about 150C.

The novel compounds of formula ll-d as well as the intermediates of formulas ll-e and III are obtained as scheme:

R2 OOH VIII II-C

wherein R,, R R R, and B each have the same meaning as hereinabove.

According to one alternative synthesis outlined above the intermediates of formula III are prepared by cyclization of a phthalimidine of formula VI. The cyclization of a phthalimidine of formula VI to form an intermediate of formula lll is readily accomplished by treatment with a Lewis acid such as titanium chloride, boron trifluoride and the like. The oxidation and reduction of the formula ll intermediates to form the desired end products is accomplished by the procedures described above.

The reaction with Lewis acid is preferably carried out in the presence of an inert organic solvent, e.g., hydrocarbon solvents such as toluene, xylene and the like, and preferably at-an elevated temperature suitably at the reflux temperature of the solvent employed. A preferred temperature range: for the cyclization of the phthalimidines is a temperature between about 50C. to about 200C. The phthalimidine intermediates of formula VI are prepared by condensing a 3-phenylphthalide of formula Vll with a-diamine of formula XII. The 3-phenylphthalides of formula Vll and the diamines of formula X employed as starting materials are known compounds or analogs of known compounds which are readily accessible in analogy to the known compounds.

The preparation of the formula VI intermediates is catalyzed by salts of organic bases as pyridine, trialkylamine, quinoline, ethylenediamine, etc., with acids such as an organic acid, a mineral acid, e.g., sulfuric acid, hydrohalic acid, phosphoric acid, perchloric acid, etc., or a Lewis acid such as zinc chloride, aluminum chloride, etc. Preferred catalysts for the reaction are the salts of ethylenediamineand pyridine such as pyridinium hydrochloride and the like. It is preferred to carry out the reaction with an excess of the ethylenediamine reactant as solvent. However, inert organic solvents such as alcohols, e.g'., methanol, ethanol, etc.; hydrocarbons, e.g., benzene,.toluene. etc., ethers, e.g., tetrahydrofuran, dioxane, etc., can'also be employed. The reaction is carried out at an elevated temperature, preferably at a temperature above 100C. Especially suitable temperatures for carrying out this reaction are temperatures between about l80C. and about 250C.

The preparation of the phthalimidines of formula VI does not itself constitute part of this invention and is given here for the sake of completeness only.

Alternatively, the intermediates of formula III can be prepared from the corresponding diazacycloalkcnylisoindolones of formula Vlll by reaction with an appropriate phenyl-organometallic derivative of the formula wherein R and R, each have the same meaning as heremabove', and Z is Li. MgBr. Mgl, MgCl or the like. The reaction with a phenyl-lithiumderivative of formula Xl can be conveniently carried out in the pres- 10 once of an inert solvent at about room temperature. Higher or lower temperatures suitably in the range of about 10C. to about C. can also be employed. Suitable solvents that can be utilized are, for example, the hydrocarbons such as benzene, toluene, xylene, etc., ethers, and the like or mixtures of such solvents.

The diazacycloalkenylisoindolone intermediates of formula Vlll are also novel compounds and thus constitute a part of this invention. They are readily prepared by the condensation of a phthalaldehydic acid deriva tive of formula lX with an alkylene diamine of formula XII. The condensation reaction is conveniently carried out in the presence of an inert organic solvent and preferably at an elevated temperature. Suitable temperatures for carrying out the condensation reaction are temperatures between about 20C. and about 100C. or the boiling point of the reaction mixture. As solvent for the condensation there can be suitably employed any of the usual organic solvents such as alcohols, hydrocarbons, ethers, etc.

The phthalaldehydic acid derivatives of formula lX are known starting materials or analogs of known compounds readily obtained by known processes.

In still'another ale'rnative process, the end products of formula I can be obtained by oxidation of a l-phenyl-2-aminoalkylisoindoline derivative as outlined be-' low:

R2 HOH Ra. Bax

R2 ax 4 V-a. 1/ ma; -B-N'H2 'cna R1. R2 N-B"NH2 wherein B, R,, R,, R, and R, are as defined hereinabove; and X is halogen, preferably chlorine, iodine or bromine or other similar leaving groups such as mesyloxy, tosyloxy and the like.

The oxidation is accomplished by treating with an oxidizing agent such as gaseous oxygen or chemical oxidants such as chromium trioxide in acetic acid and the like.

The reaction is preferably carried out in the presence of an organic solvent such as, for example, hydrocarbon solvents, e.g., benzene, tolueneor the like; alkanoic acids, e.g., acetic acid, propionic acid, etc.; ethers, alcohols and solvents such as dimethylformamide, etc. The reaction can be suitably accomplished at room temperature or at an elevated temperature, preferably at a temperature between about 20C. and lC. The l-phenyl-2-aminoalkylisoindoline intermediates are prepared from the diols of formula V via a diester of formula V-a. The diesters are obtained by the usual techniques for esterification, e.g., treating the diol with one of the ordinary esterifying agents such as a halo acid and halides such as phosphorous halide, thionyl halide, tosyl halide, etc. The diester of formula V-a is in turn converted to the l-phenyl-2-aminoalkylisoihdoline intermediate of formula VI by condensing with a diamine of formula Xll.

The reaction with diamine is coveniently carried out by adding the diester of formula V-a to the diamine at room temperature. Preferably, there is emloyed a large molar excess of diamine. The reaction can also be carried out at temperatures above or below room temperature, althouh for practical reasons it is preferred to operate at a temperature between about 0C. and 100C. The reaction is suitably carried out in the presence of an organic solvent such as, for example, benzene, methylene chloride, ether, tetrahydrofuran and the like; or, in the case where either or both of the reactants are liquid under the conditions employed in the reaction, the reaction is conveniently carried out in the absence of a solvent.

The preparation of the l-phenyl-2-aminoalkylisoindolines of formula VI does not constitute part of this invention and is given here for the sake of completeness only.

As used throughout this application the term lower alkyl" denotes straight and branched chain hydrocarbons containing 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, sec.-butyl, t.-butyl and the like. The term lower alkoxy" denotes lower alkylether groups wherein the alkyl group is as defined above. The term halogen as used herein includes all four halogens, i.e., clorine, bromine, iodine and fluorme.

Suitable salts of the compounds of formula I are prepared from nontoxic organic and inorganic acids. Suitable organic acids are, for example, malcic acid,

fumaric acid, ascorbic acid, tartaric acid, salicylic acid, succinic acid, citric acid and the like. Suitable inorganic acids are, for example, the hydrohalic acids, e.g., hydrochloric acid and hydrobromic acid; sulfuric acid, sulfamic acid, phosphoric acid, etc. The acid addition salts are readily prepared by the usual techniques for the preparation of acid addition salts which are readily apparent to those skilled in the art.

As has been indicated hereinabove the novel end products of this invention, i.e., the compounds of formula l and their pharmaceutically acceptable acid addition salts and the compounds of formula ll-d and their pharmaceutically acceptable acid addition salts, are useful as psychostimulants. When administered, for example, orally, to animals such as mice they produce a direct-acting stimulant effect of long duration in single doses in amounts ranging from .03 mg/kg to 50 mg/kg. By way of illustration the compound of Example l0, 2-(Z-benzoylphenyl)-2-imidazoline, which has an LD,, in mice of 200 mg/kg p.o.; mg/kg s.c.; 77 mg/kg i.p.; and 37 mg/kg i.v. (Proc. Soc. Exptl. Biol. Med., Vol. 57, page 261); reversed the hypothermia induced by reserpine in mice at a dose of l0 mg/kg s.c. (Med. Pharmacol. Exp., Vol. l2, pages 226-232, 1965); prevented the ptosis induced by tetrabenazene in mice at .06 mg/kg p.o. (Pletscher et al., Progress. Drug Research, Vol. II, page 417, i960); reversed the reserpine (10 mg/kg s.c.) induced sedation in mice by increasing their locomotor activity at doses of 25-50 mg/kg p.o. (Med. Pharmacol. Exp., Vol. l2, pages 226-232, 1965); and potentiated the effects of l3-(3,4- dihydroxyphenyl-a-alanine (DOPA) in mice at a dose of 6.25 mg/kg i.p. (Arc. Exp. Path. and Pharm., Vol. I40, page 237). The compounds of this invention have psychostimulant effects qualitatively similar in many respects to those of imipramine and amphetamine which are well known for their therapeutic uses and properties. Among other illustrative compounds of formulas l and ll-d which have been similarly tested and found to be qualitatively similar to 2-(2-benzoylphenyl)-2-imidazoline, there can be named by way of exemplification the following:

5-(4-chlorophenyl)-2,3-dihydro-5-hydroxy-5H- imadazo[2,l-a]-isoindole; 2,3-dihydro-5-hydroxy-5-(4-methoxyphenyl)-5H- imidazoIZ,l-al-isoindole; and 2,3-dihydro-5-methoxy-5-phenyl-5H-imidazo[ 2, l

isoindole. The activity of the claimed compounds of formulas l and ll-d first demonstrated by pharmacological evaluation in warm-blooded animals as indicated herein permits their use in therapy in the same general manner as imipramine or amphetamine, which latter compounds exhibit psychostimulant activity in the DOPA potentiation test at doses of l0 mg/kg i.p. and L0 mg/kg i.p. respectively and in the ptosis prevention test at doses of 60 mg/kg and 7.5 mg/kg respectively. As a further illustration of the psychostimulant activity of the compounds of formulas l and li-d. the compound of Example 2i. 2.3.4.5-tetrahydro-7-hydroxy-7phenyl7H- diazepino-l2,l-a1isoindole. which has an LD,,., of 40 mg/kg i.v.. prevented the ptosis induced by tctrabenazene at 0.4 mg/kg p.o.; reversed the hypothermia and hypometabolic effects induced by reserpine (l mg/kg s.c.) in mice at mg/ltg p.o.; and potentiated the effects of DOPA in mice at a dose of 7.5 mg/kg i.p. The compounds of this invention thus demonstrate a pattern of activity associated with anti-depressants of known clinical efficacy and are similarly useful as psychostimulants in the treatment of depressed states. for example, in cases of simple depression or in cases of chronic nervous exhaustion.

in addition to their use as psychostimulants. the compounds of formulas l and ll-d are useful as analgesic agents. By way of example. 2-(2-benzoylphenyl)-2 imidazoline. when submitted to standard pharmacological tests for analgesic properties. exhibited marked activity in the writhing test in mice at doses of 30.8 mg/kg p.o. and 5 mg/kg s.c. and anit-pyretic activity in rats at doses of 6.25 to 50 mglkg p.o. The compound also showed potent anti-inflammatory activity in the inflamed rat foot test at 6.25 mg/kg p.o. and antiedema activity in the Carrageenan anti-edema rat paw test at 6.25 mg/kg p.o. in the unanesthetized cat test for muscle relaxants the compound was active at a dose of 2.5 mg/kg p.o. Based on the foregoing pharmacological tests in animals. the analgesic properties of the novel end products of this invention and particularly those of 2-(2-benzoylphenylZ-imidazoline can be likened to the analgesic properties of phenylbutazone which is well known for its therapeutic uses and properties.

Compounds of formulas l and ll-d are also useful as anorexigenic agents owing to their marked activity in the 4-hour anti-obesity test in rats wherein compounds of this class have demonstrated activity qualitatively similar to amphetamine. Compounds of this series have also demonstrated useful cardiovascular properties. For example. 2-(2-benzoylphenyl)-2-imidazoline in dogs at 4mg/kg i.v. produced an increase in blood pressure of 10 mm. Hg after 2 minutes followed by gradual increase to 25 mm. Hg.

Compounds of formula I have also been found to be active as anti-fungal agents. For example. they have been found to be active in vitro in Candida albicans. Microsporum audouini and Trichophyton mentagrophytes. Accordingly, these compounds can be em ployed as anti-fungal agents in the treatment of pathogenic diseases caused by these organisms. They can. for example, be employed in the treatment of infectious fungal diseases such as moniliasis and dermatomycoses. For the treatment of fungal infections the compounds of formula I can be employed by applying a suitable composition containing about 0.1 mg. to about 5 g. of active material over the site of the infection. Suitable compositions are prepared by embodying a compound of formula I or a pharmaceutically acceptable salt thereof in a conventional carrier suitable for topical administration.

The novel end products of this invention, i.e.. the compounds of formulas l and ll-d are mostly white crystalline odorless solids melting at temperatures in the order of 200C. They have basic properties and can be conveniently preparedin the form of their acid addition salts. Suitable salts are prepared as described hereinabove. The salts are characteristically white crystalline odorless solids soluble in water and have good stability under ordinary conditions.

The compounds of formulas l and ll-d. preferably in the form of their acid addition salts can be formulated into preparations suitable for administration by enteral or parenteral routes. They can be embodied in pharmaceutical unit dosage forms containing from about 0.5 mg. to about 100 mg. of active material. Le. a compound of formulas l or ll-d or a salt thereof. Parenteral formulations will ordinarily contain less of the active substance than compositions intended for enteral. e.g.. oral. administration. For oral administration the products of this invention can be prepared as tablets, capsules and the like containing about 10 to mg. of active material. Formulations suitable for oral administration may be such as to provide either immediate. or in the alternative. sustained release of the active drug. in general. the formulations will be prepared with pharmaceutically acceptable adjuvant materials comprising from about to about 98percent of the weight of the compositions in oral dosage form.

For parenteral administration the compounds can be formulated with a liquid diluent. for example. distilled water. in the preparation of a suitable parenteral dos-.

age form. The preferred parenteral dosage form will contain from about 0.5 mg. to about l5 mg. of the active drug. in general, the compounds of this invention are formulated with conventional inert adjuvants into dosage forms suitable for enteral or parenteral administration following the conventional techniques and procedures of the prior art. Suitable dosage forms include tablets and capsules as well as solutions, emulsions and suspensions. The inert adjuvants which are suitable for use in preparing the various dosage forms include liquids and solids inorganic or organic in nature such as water. gelatin. lactose. starch, magnesium stearate. talc. vegetable oils. gums, polyalkylene glycols, Vaseline, etc. Additionally. the compounds can be used in combination with preservatives. stabilizers. wetting or emulsifying agents. salts for altering the osmotic pressure. buffers. etc. if desired. the compounds can be used also in admixture with other therapeutically valuable substances. Specific embodiments showing illustrative formulations of an exemplary compound of formula I follow.

Tablet Formulation Per Tablet 2-(Z-benzoylphenyl)-2-imidazoline 10.0 mg. Lactose ll3.5 mg. Corn Starch 70.5 mg. Prcgelatinized Corn Starch 8.0 mg. Calcium Stearnte 3.0 m

Total Weight 205.0 mg

Procedure Suppository Formulation Per L3 Gram Suppository 2-(Z-benzoylphenyl)-2-imidazoline 0.025 gram Wccobce M (E. F. Drew Company L230 gram 522 Fifth Avenue New York. New York) Carnauba Wux 0.045 gram Procedure 1. The Wecobee M and the carnauba wax were melted in a suitable size glass-lined container (stainless steel may also be used). mixed Welland cooled to 45C.

2. 2-(2-Bcnzoylphenyl)-2-imidazoline. which had been reduced to a fine powder with no lumps. was added and stirred until.. completely and uniformly dispersed.

3. The mixture was poured into suppository molds to yield suppositories having an individual weight of 1.3

grams.

4. The suppositories were cooled and removed from molds. They were individually wrapped in wax paper for packaging. (Foil may also be used.)

Capsule Formulation Per Capsule 2-(Z-benzoylphenyl)-2-imidazoline 25 mg. Lactose 158 mg. Corn Starch 37 mg.. Talc 5 mg. Total Weight 255 mg.

Procedure l. 2-(2-Benzoylphenyl)-2-imidazoline was mixed with the lactose and corn starch in a suitable mixer.

2. The mixture was further blended by passing through a Fitzpatrick Comminuting Machine with a No. lA'screen with knives forward.

3. The blended powder was returned to the mixer. the tale added and blended thoroughly. The mixture as then filled into No. 4 hard shell gelatin capsules on a Parke Davis eapsulating machine (any similar type machine may be used).

Parenteral Formulation Per cc.

2-(2-benzoylphenyl)-2-imidazoline 2.5 mg. Tartaric Acid q.s. ad pH 3.0 Phenol Anhydrous 4.5 mg. Water for Injection. U.S.P. q.s. ad l.0 cc.

Procedure sive amounts of fibers were rejected.

The drug was prepared in duplex ampuls. one containing the dry drug and the other containing the special diluent.

Dr Fill Am ul 5 cc.

2-( Z-hen-mylphenyl )-2'imidamlinc 25 mg.

A parenteral grade of the drug. fiber-free. was filled into the ampul using a Diehl Mater electric filler or other suitable type filler. The ampuls were sealed and sterilized at 255F. for 2 hours.

Immediately before use the powder was solubilized with the following solution:

Special Diluent 2 cc.

in a suitable container under an atmosphere of nitrogen the tartaric acid was dissolved in part of the water for injection. The solution was made to volume, filtered through an 02 Selas candle filter and filled into 2 cc. flint ampuls. The filling should be done under an atmosphere of nitrogen. The ampuls were sealed and sterilized at 2l2F. for 30 minutes. The ampuls were then inspected and those that leaked or contained fibers were discarded.

The drug in the preferred oral dosage form. i.e., tablets or capsules containing 10 to 25 mg. of active material, will be administered under ordinary circumstances three or four times daily. The parenteral composition will be administered ordinarily one or two times daily. Effective dosages for the administration of compounds of this invention, i.e.. the compounds of formulas l and ll-d. will. of course. depend in all instances upon the severity and individual characteristics of each case as determined by the prescribing practitioner. it will be understood that dosage forms containing larger and smaller quantities of the active drug ingredient are encompassed by the scope of this invention and that such dosage forms can be administered more or less frequently than indicated heretofore. it will be understood that dosage forms containing inert adjuvants in quantities which are greater or less than those indicated heretofore are also encompassed by this invention.

The invention will be more fully understood from the examples which follow. These examples are illustrative of the invention and are not to be construed as limitative thereof. All melting points are in degrees centigrade. Decomposition melting points were taken in a Thomas Hoover apparatus in open capillaries. They may vary tl0 depending on the rate of heating. 1 EXAMPLE 3 Preparation of Z-benzoylbenzaldehyde A mixture of l g. of selenium dioxide and l g. of 2-hydroxymethylbenzhydrol in 5 ml. of acetic acid was refluxed for 4% hours. The solution was cooled. filtered from selenium and the filtrate was poured into ice water and made alkaline with sodium hydroxide. Extraction with ether gave a yellow oil to which petroleum ether was added. White prisms were obtained which melted at 64-67. Ultraviolet maximum (2- propanol) at 226/7 u (e l5.750) and 251/2 t (e 18.500). inflexion at 294 p. (e 2600); infrared absorption (CHCl at I665 em" and 1705 cm".

Anal. Calcd. for C H O C. 79.98; H, 4.79. Found: C. 80.00; H. 4.68.

17 EXAMPLE 2 Preparation of Z-(p-chlorobenzoyl)-benzaldehyde A solution of 18.6 g. of 4'-chloro-2-hydroxymethylbenzhydrol in 100 ml. of acetic acid and 10.4 g. sele- 5 recrystallization from a mixture of ether and petroleum ether gave 2-(p-chlorobenzoyl)-benzaldehyde melting at 1 l2-1 13. Ultraviolet inflexion (2-propanol) at 225 .t (e 17,500) and maximum at 259 p. (e 22,500),

infrared absorption (CHCI) at 1670 cm and 1705 Anal. Cald. Calcd. c,,u,cio,= C, 68.72; H, 3.71. Found: C, 69.12; H, 3.50.

EXAMPLE 3 Preparation of 2-(p-anisoyl)-benzaldehyde A solution of 26 g. of 4'-methoxy-2-hydroxymethylbenzhydrol in 140 ml. of acetic acid and 14.5 g. selenium dioxide was refluxed for 2 hours. The mixture was filtered and the filtrate was made basic. An oil separated which crystallized on standing and was collected. Recrystallization from a mixture of methylene chloride and petroleum ether gave off-white platelets melting at 90-91. Ultraviolet maxima (2-propanol) at 221 p. (e 21,600), 258 p. (e= 12,400) and 292 p. (e= 17,000); infrared absorption (CHCl at 1660 cm and at 1700 cm.

Anal. Calcd. for c,,a,,o,= c, 74.99; H, 5.03. Found:

EXAMPLE 4 Preparation of 2-benzoyl-4-chlorobenzaldehyde A solution of 9.3 g. of 5-chloro-2-hydroxymethylbenzhydrol in ml. of acetic acid and 5.2 g. of selenium dioxide was refluxed for 3 hours. The mixture was filtered, cooled, poured on ice, made alkaline and extracted with ether. Concentration and addition of petroleum ether gave the product as prisms which after 45 recrystallization from a mixture of ether and petroleum ether melted at 82-84. Ultraviolet maxima (2- propanol) at 230 p. (e 19,500) and 257 p. (e 23,500); infrared absorption (CHCl,) at 1675 cm" and 1705 cm".

Anal. Calcd. for C H,ClO,: C, 68.72; H, 3.71. Found: C, 69.05; H, 3.87.

EXAMPLE 5 Preparation of 2-(4-bromobenzoyl)-benzaldehyde To a stirred solution of 8.2 g. of lithium aluminum hydride in 180 ml. of tetrahydrofuran was added 40 g. of 2-(4'bromobenzoyl)benzoic acid in the course of 30 minutes. The mixture, after being kept at 25 for 2 dition of petroleum ether gave white prisms melting at l03-l09. Recrystallization from a mixture of other and petroleum ether raised the melting point to 1 10- 113. Ultraviolet inflexion (Z-propanol) at 225 a (e 17,500) and maximum at 261 p. (e 22,200); infrared absorption (CHCl at 1675 cm" and 1705 cm".

Anal. Calcd. for C,,H,,Br0,: C, 58.16; H, 3.14. Found: C, 57.86; H, 3.41.

EXAMPLE 6 Preparation of 2,3-dihydro-5-phenyl-5H-imidazo[2,1-a]isoindole sulfate from 2-benzoylbenzaldehyde A solution of 21 g. of o-benzoylbenzaldehyde in 250 m1. of toluene and 34 ml. of ethylenediamine was refluxed for 24 hours. During this time 11.5 ml. of an aqueous phase was separated in a Dean Stark receiver. The reaction mixture was concentrated in vacuo to an orange oil which was dissolved in ethyl acetate and washed twice with water. The solution was dried and concentrated, dissolved in 200 ml. of ethyl acetate and a solution of 5.3 ml. of concentrated sulfuric acid in ml. of ethanol was added. A crystalline precipitate was collected which after recrystallization from a mix ture of methanol and ethyl acetate gave white prisms melting at 226-229 dec. Ultraviolet maxima (2- propanol) at 240 p. (e= 15,000) and 276 p. (e= 5,400); infrared absorption (KBr) 1660 cm".

Anal. Calcd. for C, H,,N,-H SO,: C, 57.82; H, 4.85; N, 8.43. Found: C, 57.61; H, 4.81; N, 8.73.

The hydrochloride of 2,3-dihydro-5-phenyl-5H- imidazo[2,l-a]isoindole was prepared from the corresponding base with aqueous l N hydrochloric acid. On recrystallization from a mixture of methanol and toluene, white prisms melting at 226228 dec. were obtained. Nmr peaks (DMSO) at 8 3.6-4.6 (4H, multiplet), at 6 6.13 (1H, singlet), at 8 7.3-7.9 (9H, multi- 0 plet).

EXAMPLE 7 Preparation of 2,3-dihydro-5-phenyl-5H-imidazoI2,1-a]isoindole sulfate from 2-(Z-aminoethyl)-3-phenylphthalimidine ide. The solution was extracted with ethyl acetate and the extract was concentrated. Addition of a solution of sulfuric acid in a mixture of ethanol and tetrahydrofuran and further dilution with ethyl acetate gave a crystalline precipitate. Recrystallization from a mixture of methanol and ethyl acetate gave the product as white prisms melting at 225-228 dec.

EXAMPLE 8 Preparation of 2,3-dihydro-5-hydroperoxy-5-phenyl-5H-imidazol2,1-

alisoindole The base liberated from 16.6 g. of2,3-dihydro-5-phenyl-5H-imidazo[2,l-a]isoindo1e sulfate was dissolved in 50 m1. of ethanol and 11 ml. of a 30 percent by weight aqueous solution of hydrogen peroxide was added. The mixture was stirred at 25 for 40 hours. A

crystalline crop was collected and placed on a column containing 250 g. of silica gel. Elution with a mixture of I part of methanol (volume) and 1 part of chloroform (volume) gave fractions from which on concentration a crystalline residue was obtained. Recrystallization from a mixture of methanol and chloroform gave the product as white prisms melting at l67-l68 dec. Ultraviolet inflexions (2-propanol) at 232 p. (e 14.000) and 290 a (e= 2600). maxima at 269 y. (e'= 4000) and 275 a (e 4400), infrared absorption (KBr) at 1665 cm".

Ana. CalCCl. for cmHuNzoz: C. H. N, 10.52. Found: C. 72.09; H. 5.39; N, 10.22.

The hydrochloride of 2,3-dihydro-5-hydroperoxy-5- phenyl-5l-1-imidazo[2,1a]isoindole was prepared with methanolic hydrogen chloride and after recrystallization from a mixture of methanol and ether gave white platelets melting at 158 1599, dec. Ultraviolet maxima (Z-propanol) at 245 p. (e ="14,800) and 278 p. (e 5200); infrared absorption (KBr) at 1680 cm.

Anal. Calcd. for c,.H,.N,o,-Hcl: C, 63.47; H 4.99: C1. 11.71. Found: C, 63.63; 11.4.83; Cl, 11.79.

EXAMPLE 9 Preparation of 5-(p-chlorophenyl)-2,3-dihydro-5-hydroperoxy-5 H- imidazo[2,l-a]isoindole hydrochloride 1 Gram of 2-(p-chlorobenzoyl)-benzaldehyde was thoroughly mixed with 0.9 g. of ethylenediamine toluene sulfonate and heated in a metal bath (bath temperature. 120-l25) for 1 minute. On cooling a deep yellow glassy material was obtained which on addition of methylene chloride, ethyl acetate and petroleum ether gave a crystalline precipitate which was treated with ice cold aqueous sodium hydroxide. The mixture was extracted with ether and the extract was exposed to air at 25 for 18 hours. A crystalline crop was collected and suspended in methylene chloride. Addition ofethereal hydrogen chloride gave a crystalline material which after recrystallization from a mixture of methanol and ether gave white prisms melting at 175-l77 dec. Ultraviolet inflexion (2-propanol) at 223 a (e 21.800) and 279 p. (e 5600), maximum at 243 p. (e 15,500): infrared absorption (KBr) at 1670 cm.

Anal. Calcd. for C H, CIN,O,-HCI: C, 56.99; H. 4.18; CI, 21.03; N, 8.31. Found: C, 57.14; H, 4.15; C1. 21.02; N. 8.30.

EXAMPLE 10 Preparation of 2-(2-benzoy1phenyl)2imidazoline from 2,3-dihydro-5-phenyl-5 H-imidazo[2,'l-a]isoindole To a suspension of 8.5 g. of 2,3-dihydro-5-phenyl- 5H-imidazo[2.1-a]isoindo1e sulfate'in water was added 50 ml. of 1N aqueous sodium hydroxide. Extraction with methylene chloride and concentration gave an orange oil which was dissolved in a mixture of '30 m1. of methylene chloride and 30 ml. of ethanol. .To this solution was added 2.3 ml. of 30 pereent'by-weight hydrogen peroxide. After stirring at 25 for 18 hours. a precipitate was collected which after recrystallization from methanol gave white prisms melting at 194-196 dec. Ultraviolet .inflexions (2-propanol) at 225 p. (e' 15.500) and 290 p. (c 2250), maxima at 269 p. (e 4100) and 276 p. (e 4250); infrared absorption (KBr) 1660 em".

Anal. Calcd. for C H MO: C. 76.78; H. 5.64; N. 11.19. Found: C. 76.42; H. 5.79; N. 11.13.

The 2-(2-benzoylphenyl)Q-imidazoline prepared in this manner can form the isomeric 2.3-dihydro-5- hydroxy-5-phenyl-5H-imidazo[2.1-a]isoindole.

The hydrochloride was prepared by adding a solution of hydrogen chloride in methanol to a suspension of 2-(2-henzoylphenyl)-2-imidazoline in methanol. Ether was added and the crystalline precipitate was collected. Recrystallization from a mixture of methanol and ether gave white prisms melting at 173-176 dec. Ultraviolet maximum (2-propanol) at 252 p. (e 13.600 infrared absorption (KBr) at 1665 cm.

Anal. Calcd. for C H MO'HCl: Cl, 12.36. Found: Cl, 12.22.

The hydrobromide was prepared by adding an aqueous solution of hydrobromic acid to a suspension of 2-(2-benzoylphenyl)-2-imidazoline in ethanol. Addition of ether gave a precipitate which after recrystallization from a mixture of ethanol and ether gave white platelets melting at,193194 dec.

Anal. Calcd. for C H N oHBrz Br. 24.13. Found: Br, 24.15.

EXAMPLE 1 1 Preparation of 2-(2-benzoy1phenyl)-2-imidazo1ine from 2,3-dihydro-S-hydroperoxy-S-phenyl-SH-imidazoI2. 1 a]isoindole A solution of 0.7 g. of sodium sulfite heptahydrate in 3 ml. of water was added to 0.5 g. of 2,3-dihydro-5- hydroperoxy-S-phenyl-SH-imidazo[2.l-a]isoindole in 7 ml. of dimethylformamide. The solution was heated to 100 for 15 minutes. On cooling and addition of 20 ml. of water, 2-(2-benzoylphenyl)-2-imidazoline was obtained.

EXAMPLE 12 Preparation of 2-(2-benzoy1phenyl)-2-imidazoline from 2,3-dihydro-5-hydroperoxy-5-phenyl-5H-imidazo[2.1-

a]isoindole A solution of 0.1 g. of 2,3-dihydro-S-hydroperoxy-S- phenyl-5H-imidaz0[2.l-a]isoindole and 0.33 g. of triethylphosphite in 20 ml. of ethanol was kept on a steam bath for 5 minutes, then 18 hours at 25. The solution was concentrated in vacuo and on addition of water 2-(2-benzoylpheny1)-2-imidazoline was obtained.

EXAMPLE 13 Preparation of 2-(Z-benzoylphenyl)-2-imidazo1ine from 2-(2-aminoethyl)-1-phenylisoindoline A solution of 3.3 g. of chromium trioxide and 5.9 g. of 2-(2-aminoethyl)-1-phenylisoindoline in 250 ml. of acetic acid was stirred at 5S-60 for 18 hours. The solution was cooled. poured on ice and made alkaline. Extraction with methylene chloride and removal of the solvent gave a brown 011 which partly crystallized. Recrystallization from a mixture of chloroform and ethyl acetate gave the product as white prisms melting at 194-196 dec.

EXAMPLE 14 Preparation of 2-(2-aminoethyl)-l-phenylisoindoline A solution of 127 g. (0.59 mole) of 2-hydroxymethylbenzhydrol was dissolved in 900 ml. of benzene. g. of anhydrous magnesium sulfate was added and the mixture was cooled in an ice bath. Hydrogen bromide was bubbled into the stirred solution until saturation which took about 30 minutes. During this time the temperature of the solution was kept at 15-18. The ice bath was removed and the temperature was allowed to rise to 35 in the course of 1 hour. The mixture was heated for another hour at 4()-45 on a steam bath.

During the whole time hydrogen bromide was passed into the solution to keep it saturated. The mixture was filtered and the solution'was concentrated in vacuo to give a red oil which was dissolved in 200 ml. of benzene and added to 342 g. (5.7 moles) of ethylenediamine in the course of 15 minutes. During the addition the mixture was stirred and cooled to maintain a temperature of ca. 40 The mixture was stirred at 25 for 70 minutes. Two layers were obtained and separated. The benzene layer was washed with water and concentrated in vacuo. The residual oil was dissolved in 250 ml. of ether. This solution was extracted twice with 300 ml. of cold lN hydrochloric acid. The acidic aqueous phase was made alkaline with aqueous sodium hydroxide and extracted with 350 ml. of ether. The ethereal solution was washed with 250 ml. of water, dried and concentrated. The residue was an amber oil which crystallized on scratching. This material melted up to ca. 45.

By analogy there were also prepared the following:

2-( 3-aminopropyl)- l -phenylisoindoline 2-(2-aminoethyl)-6-chloro-l-phenylisoindoline 2-(2-aminoethyl)-l-(p-methoxyphenyl)isoindoline 2-(4-aminobutyl l -phenylisoindoline 2-(2-amino-2-methylpropyl)-l-phenylisoindoline 2-( 2-aminopropyl l -phenylisoindoline 2-( 2-aminoethyl)-l-(p-hydroxyphenyl)isoindoline.

EXAMPLE l5 Preparation of 2-[2'-(4-chlorobenzoyl )phenyl ]-2-imidazoline To 1 ml. of ethylenediamine was added 1 g. of 2-(pchlorobenzoyl)-benzaldehyde in small portions. An

exothermic reaction took place and after 5 minutes the reaction mixture was poured into ice water. A'yellow solid precipitate was collected and dissolved in methylene chloride. Ether and petroleum ether were added and the solution was shaken in air at 25. A crystalline precipitate was obtained which after recrystallization from a mixture of methylene chloride and methanol gave white needles melting at l78-l80 dee. Ultraviolet maxima (2-propanol) at 223 p. (e 21,250), 268 p. (c 4300), 275 p. (e I 4320), inflexion at 290 p. (e 2200); infrared absorption (KBr) at I660 cm".

Anal. Calcd. for C,.H ClN,O: C, 67.49; H, 4.60. Found: C, 67.38; H, 4.56.

The 2-[2'-(4-chlorobenzoyl)phenyl]-2-imidazoline prepared in this manner can form the isomeric 5-(4- chlorophenyl)-2,3-dihydro-5-hydroxy-5H- imidazo[2,l-a]isoindole.

The hydrochloride was prepared by adding a solution of hydrogen chloride in ether to a suspension of 5-(4- chlorophenyl)-2,3-dihydro-5-hydroxy-5H- imidazol 2,l-a]isoindole. After stirring for 30 minutes a crystalline crop was collected and recrystallized from a mixture of cloroform and ether to give white prisms melting at l68-l7l dee. Ultraviolet inflexion (2- propanol) at 220 p. (e 22,000), maxima at 252 p. (e 12.900), 266 p. (s l3,000); infrared absorption (KBr) at i670 cm.

Anal. Calcd. for C H ClMO'HCl: Cl. 22.08. Found: Cl, 22.18.

EXAMPLE 16 Preparation of 2-[2"(4-anisoyl)phenyl1-2-imidazoline To 4 ml. of ethylenediamine was added 2 g. of 2-(panisoyl)-benzaldehyde in small portions; The solution was stirred for l0 minutes, poured into ice water and extracted with methylene chloride. The methylene chloride solution was concentrated. the residue was dissolved in ethanol and a stream of air was passed through the solution for 18 hours. A crystalline precipitate was collected and after recrystallization from a mixture of chloroform and ether gave white prisms melting at l7l-l74 dee. Ultraviolet maxima (2- propanol) at 227 p. (e 20,200), 277 u (e 8800), 282 p. (e 8750), inflexion at 292 p. (e 7200); infrared absorption (KBr) at 1660 cm".

Anal. Calcd. for C H N O z C, 72.84; H, 5.75; N, 9.99. Found: C, 73.07; H, 5.71; N, 9.83.

The 2-[2'-(4-anisoyl)phenyll-Z-imidazoline prepared in this manner can form the isomeric 2,3-dihydro-5-hydroxy-5-(4-methoxyphenyl )-5 H-imidazo[ 2, l alisoindole.

EXAMPLE 17 Preparation of 2-[4'-chloro-2'-benzoylphenyl1-2-imidazoline To 2 ml. of ethylenediamine was added 0.9 g. of 2-benzoyl-4-chlorobenzaldehyde in small portions. The solution was stirred'for 10 minutes, poured into ice water and the solid yellow precipitate was collected.

This solid was dissolved in ether and shaken in air for' EXAMPLE l8 Preparation of 2-[2-(4-bromobenzoyl)phenyl1-2- imidazoline A solution of 6 g. of 2-(4-bromobenzoyl)-benzaldehyde and 6.6 ml. of ethylenediamine in 50 ml. of toluene was refluxed for IS hours. During this time 0.5 ml. of an aqueous phase had separated in a Dean Stark receiver. The mixture was concentrated in vacuo and the residual orange. oil was dissolved in a mixture containing l5 ml. of ethanol, l5 ml. of methylene chloride and 1.5 ml. of a 30 percent by weight aqueous solution of hydrogen peroxide. After stirring at 25 for 18 hours a white precipitate was collected which after recrystallization from methanol gave white needles melting at l87-l89 dec. Ultraviolet maxima (2-propanol) at 227 p. (e 22,800), 259 p. (e 4700), 275 p. (e 4800), inflexion at 292 p. (e 2300); infrared absorption (KBr) at l660 cm".

Anal. Calcd. for cmHmBrNgoi C, 58.37; H, 3.98. Found: C, 58.27; H, 3.75.

The 2-[2-(4-bromobenzoyl)phenyll-2-imidazoline prepared in this manner can form the isomeric 5-(4- bromophenyl)-[2,3-dlhydro-S-hydroxy-SH- imidazo[2.l -a]isoindole.

The hydrochloride was prepared by adding ethereal hydrogen chloride to a solution of 5-(4-bromophenyl)- 2,3-dihydro-5-hydroxy-5H-imidazo[2,l-a]isoindole in a mixture of methylene chloride and methanol. The precipitate was recrystallized from a mixture of ethanol and ether to give white prisms melting at l55l58 dee. Ultraviolet inflexion (2-propanol) at 223 p. (e 20,000); maxima at 251 p. (e= 12.200) and 27l p. (e

23 13,300); infrared absorption (KBr) at 1660 cm.

Anal. Calcd. for C,,,H, -,BrN O'HCl: Cl, 9.70. Found: Cl. 9.82.

EXAMPLE 19 Preparation of 2,3-dihydro-5-methoxy-5-phenyl-5 H-imidazo[ 2,1-

aIisoindole hydrochloride A solution of 5 g. of 2-(2-benzoylphenyl)-2-imidazoline in 50 ml. of methanol was refluxed for 18 hours. The solution was concentrated in vacuo, dissolved in ml. of methanol and 60 ml. of ether was added. Crystals precipitated and were identified as starting material. The mother liquor was concentrated and the residue was recrystallized from a mixture of methanol, methylene chloride and ether to give the product as white prisms melting at l39-14l dec. Ultraviolet maxima (2-propanol) at 244 p. (e= 14,400) and 278 p. (e 5100); infrared absorption (KBr) at 1670 cm.

Anal. Calcd. for C,-,H N,O'HCl: C, 67.83; H, 5.70; OCH 10.32. Found: C, 67.84; H, 5.6l',OCH 10.44.

The corresponding base was obtained as a colorless oil by liberating it from the hydrochloride obtained as above with alkali. Ultraviolet inflexions (0.lN KOH) at 230 (e 14,600), 290 y. (e 2700), maxima at 269 (e 4200) and 275 p. (e 4600).

Infrared absorption (smear) at 1660 cm" and nmr peaks (CDCl;,) at 6 3.12 (3H, singlet, OCH 8 2.6-3.5 (2H, multiplet, N-CH 8 4.2-4.5 (2H, multiplet, N-CH,), 6 32 7.1-8.0 (9H, multiplet, aromatic CH).

EXAMPLE 20 Preparation of 2.3 ,4,6-tetrahydro-6-phenylpyrimido[ 2,l-a]isoindole sulfate A solution of 10.5 g. of Z-benzoylbcnzaldehyde and.

22 ml. of propylenediamine in 125 ml. of toluene was refluxed for 18 hours. During this time 4.5 ml. of an aqueous phase had separated in a Dean Stark receiver. The solution was concentrated in vacuo and the residue was recrystallized from a mixture of ethanol and petroleum ether to give white prisms melting at l70-l72 dec. Ultraviolet maximum (2-propanol) at 238 p. (e 18,200), inflexions at 246 p. (e 16,000), 265 y. (2 5600), 276 p. (e 3400) and 285 p. (e 2100); infrared absorption (KBr) at 1675 cm".

Anal. Calcd. for C,,H ,N,-H,SO,: C, 58.94; H, 5.24. Found: C, 58.62; H, 5.49.

EXAMPLE 21 Preparation of 2,3 ,4,S-tetrahydro-7-hydroxy-7-phenyl-7H- diazepino[2,1-alisoindole A solution of 10.5 g. of Z-benzoylbenzaldehyde and 28.5 ml. of 1,4-diaminobutane in 100 ml. of toluene was refluxed for 18 hours. During this time 2.5 ml. of an aqueous phase had separatcdin a Dean Stark receiver. The solution was exposed to air for 60 hours, concentrated and diluted with 300 ml. of carbon tetrachloride. A crystalline precipitate was obtained which was suspended in 40 ml. ofethanol. A solution of 1.9 g. of oxalic acid in 40 ml. of methanol was added and the solution was concentrated and diluted with ether. The precipitate was collected and recrystallized from a mixture of methanol and ether to give the oxalic acid salt as white prisms melting at ca. 200 dec. This salt was suspended in a mixture ofaqueous sodium carbonate solutuion solution methylene chloride. The methylene chloride solution was concentrated and the residue was recrystallized from a mixture of chloroform and ether to give the product as white needles melting at 216-220 dec. Ultraviolet maxima (2-propanol) at 258 a (e= 5000), 265 p. (e 5100), 273 a (e 4800), inflexions at 230 p. (e 15,000), 290 p. (e 2400); infrared absorption (KBr) at 1650 cm.

Anal. Calcd. for c u u o. C, 77.67; H, 6.52; O, 5.75. Found: C, 77.64; H, 6.75; 0, 5,64.

EXAMPLE 22 Preparation of 2-( Z-aminoethyl )-3-phenylphthalimidine A solution of 25 g. (0.1 mole) of l,2,3,9b-tetrahydro- 9b-phenyl-5H-imidazo[2,1-a1isoindol-5-one in 150 ml. of acetic acid containing 2.5 g. of hydrogen chloride was shaken under one atmosphere of hydrogen at 25 using 0.5 g. of platinum oxide as catalyst. 1n the course of 7 hours, 3000 ml. of hydrogen (theory ca. 2500 ml.) was absorbed and the rate of uptake had slowed down considerably. The solution was poured into ice water, basified with ammonia and extracted with methylene chloride. The organic phase was dried and concentrated. The residue crystallized with ether and after recrystallization from a mixture of methylene chloride and petroleum ether gave white prisms of 2-(2-aminoethyl)-3-phenylphthalimidine melting at -93. 7 1685 cm", 247 a, e 6000, 279 u, e

Anal. Calcd. for C H N O: C, 76.16; H, 6.39. Found: C, 75.81; H, 6.32.

EXAMPLE 23 Preparation of 2-[2-( Z-chlorobenzoyl )phenyl1-2-imidazoline To 250 ml. of concentrated sulfuric acid was added, with stirring and slight cooling, 37.5 g. (0.545 mole) of sodium nitrite. To this was added 120.5 g. (0.50 mole) of 2-(2-aminobenzoyl)benzoic acid at such a rate that the temperature of the reaction mixture remained between 30-40. After the addition was complete the reaction mixture was stirred for 1 hour and then poured into one liter of ice and water and filtered. The filtrate was added rapidly to a stirred solution of 55 g. (0.555 mole) of cuprous chloride, g. of sodium chloride, 250 ml. of concentrated hydrochloric acid and 300 ml. of water. The precipitated gum was extracted with chloroform and the extracts were washed twice with water, dried over anhydrous sodium sulfate and evaporated under vacuo to leave a red oil which crystallized upon scratching. Recrystallization from 200 ml. of ethyl acetate gave 2-(2-chlorobenzoyl)benzoic acid as a pink solid. A sample recrystallized three times from ethyl acetate gave colorless prisms, double m.p. 1l2-l16 and l24-126.

To a stirred suspension of 22.8 g. (0.60 mole) of lithium aluminum hydride in 700 ml. of dry tetrahydrofuran was added 104 g. (0.40 mole) of 2-(2-chlorobenzoyl)benzoic acid prepared as above in portions keeping the reaction mixture temperature between 15-30' with ice cooling. After the addition was complete the reaction mixture was stirred for one hour. Ether (400 ml.) was added followed by the slow addition of 80 m1. of water, with ice cooling. The mixture was filtered through a large sintered glass funnel which contained a matting of Celite filter-aid. The filtered solids were washed with tetrahydrofuran and the combined filtrates were evaporated under vacuo to a yellow oil which crystallized upon scratching. The material was recrystallized from 150 ml. of isopropyl ether to give 2-chloro-2'-hydroxymethylbenzhydrol as a slightly pink solid, m.p. 85-87. A sample was recrystallized 3 times from isopropyl ether to give colorless prisms, m.p. sew-s7.

A Z-liter, 3-necked, round bottomed flask was fitted with a mechanical stirrer, dropping funnel and a Dean- Stark trap fitted with a condenser. A mixture of 41.7 g. (0.376 mole) of selenium dioxide in 150 ml. of acetic acid and 300 ml. of xylene was refluxed for l5 minutes. To the boiling mixture was added dropwise during one hour, a solution of 74.4 g. (0.3 mole) of 2-chloro-2'- hydroxymethylbenzhydrol prepared as above in 85 ml. of acetic acid and 250 ml. of xylene. The Dean-Stark trap was cooled during this time to promote separation of an aqueous phase. About 60 ml. of the aqueous phase was separated during 5 hours. The reaction mixture was refluxed for a total of 22 hours, cooled and filtered.- The filtrate was added to 800 ml. of ice and water, made alkaline with 50 percent sodium hydroxide and the mixture extracted wtih 600 ml. of ether. The extracts were washed with water, dried over anydrous sodium sulfate and evaporated to yield an orange oil which could not be crystallized. Vapor phase chromatographic analysis showed the presence of two compounds.

45.4 Grams of the oil, 52.5 g. (0.875 mole) of ethylcnediamine and 400 ml. of benzene were refluxed for 5 hours in a round bottomed flask equipped with a Dean- Stark trap and a condenser. About 6 ml. of aqueous phase separated in the trap. The reaction muxture was cooled, washed three times with saturated aqueous salt solution and dried over anhydrous sodium sulfate. Air was then bubbled through the benzene solution for l5 hours but only a small amount of solid separated.

The benzene was removed under vacuo and the residue was dissolved in 150 ml. of ethanol and 40 ml. (0.350 mole) of percent hydrogen peroxide. After stirring for 3 hours the ethanol was removed under vacuo and 300 ml. of benzene was added to the residue. The aqueous phase was separated and the benzene solution was dried over anydrous sodium sulfate and evaporated under vacuo to leave a pale yellow oil. Ether 150 ml.) was added and a crystalline solid separated. The mixture was filtered to give a pale yellow solid, m.p. l64-l 67 dec. The ether filtrate was stirred at room temperature, exposed to air, for two days. The precipitated solid was filtered to give an additional pale yellow solid. Thin layer chromatography of the combined solids showed the presence of one major component, Rf 0.41, and a minor component, Rf 0.67. The latter component was 2,3-dihydro-5-hydroperoxy-5-(ochlorophenyl)-5H-imidazo[2,l-al-isoindole since the yellow solid precipitated iodine from a saturated methanolic potassium iodide solution.

To s suspension of the yellow solid in 60 ml. of refluxing methanol was added a solution of 4.28 g. (0.017 mole) of Na SO -7H,O in 30 ml. of water over a period of 5 minutes. After refluxing for IS minutes longer the reaction mixture was cooled and filtered. The filtered solid was washed 3 times with 20 ml. of water and dried. Recrystallization from methanol-chloroform 26 gave 2-[2-(2-chlorobenzoyl)phenyll-Z-imidazoline as colorless prisms, m.p. l-l8l dec.

Anal. Calcd. for C H ClN O: C, 67.49; H, 4.60; N, 9.84. Found: C, 67.15; H, 4.56; N, 9.66.

The 2-[2-(2-chlorobenzoyl)phenyll-Z-imidazoline prepared in this manner can form the isomeric 2,3- dihydr05-hydroxy-5-(2'-chlorophenyl)-5H- imidazo[2,l-a]isoindole.

To a hot solution of 6.0 g. (2| .2 mmoles) of 2-[2-(2- chlorobenzoyhphenyll-2-imidazoline in 25 ml. of 6 N methanolic hydrogen chloride and 35 ml. of methanol was added 200 ml. of ether and the solution cooled. Filtration gave 2-[2-(2-chlorobertzoyl)phenyl1-2- imidazoline hydrochloride, m.p. l78-l80 dec. Dilution of the mother liquors with 200 ml. of ether followed by cooling and filtering afforded an additional quantity of hydrochloride. Recrystallization from methanol-ether gave colorless prisms, m.p. l78-l 80 dec.

Anal. Calcd. for C H Cl N O: Cl, 22.08 Found: CL, 22.00.

EXAMPLE 24 Preparation of 2-(2- benzoylphenyl)-2-imidazoline via 1,2,3 ,9b-tetrahydro-5H-imidazo[ 2, l -a]isoindol-5-one A solution of 7.5 g. of phthalaldehydic acid in 30 ml.

of ethanol and 34 ml. of ethylenediamine was refluxed for l6 hours. The solution was concentrated in vacuo and the residue was dissolved in methylene chloride. The solution was washed with water, dried and concentrated. The residue was distilled in a bulb tube at 0.3 mm at a bath temperature of l50-l 80. A colorless oil was obtained which was dissolved in methanol and on addition of ethereal hydrogen chloride gave white prisms of l,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5one hydrochloride, m.p. 222-224 dec.

The salt obtained in the preceding experiment was treated with aqueous potassium carbonate solution. Extraction with methylene chloride gave an oil of which 0.9 g. was dissolved in a mixture of 25 ml. of benzene and 10 ml. of ether. To thissolution was added 5.5 ml. of a 2 N solution of phenyl lithium in a mixture of benzene and ether (7:3). After stirring at 25 for 1 hour the solution was poured into ice water and extracted with ethyl acetate. This solution was concentrated and the residue was exposed to air for 48 hours. On addition of methylene chloride crystals were obtained which were dissolved in methanol. Addition of ethereal hydrochloric acid gave white prisms which after recrystallization from a mixture of methanol and other gave crystals melting at l73-l75 dec. This material was identical with authentic 2-(2-benzoylphenyl)-2-imidazoline hydrochloride.

We claim:

I. A process for the preparation of a compound of the formula wherein B represents an alkylene chain of 2 to 4 carbon atoms in which one or more of the hydrogens can be replaced by lower alkyl; and R R R and R are each independently selected from the 5 wherein B, R R R and R are as defined hereinabove with a reducing agent selected from the group consisting of sodium sulfite and trialkyl phosphite. group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy. and trifluoromethyl and the tautomers thereof, which comprises treating a hydroperoxy derivative of the formula:

in NJ a OOH 

1. A PROCESS FOR THE PREPARATION OF A COMPOUND OF THE FORMULA 